Heteroaryl-linked 5-(1H-benzimidazol-1-yl)-2-thiophenecarboxamides: Potent inhibitors of polo-like kinase 1 (PLK1) with improved drug-like properties

Rheault, Tara R.; Donaldson, Kelly H.; Badiang-Alberti, Jennifer G.; Davis‐Ward, Ronda G.; Andrews, Chandler; Bambal, Ramesh; Jackson, Jeffrey R.; Cheung, Mui

doi:10.1016/j.bmcl.2010.06.009

Cited by 15 publications

(16 citation statements)

References 23 publications

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“…The former was much more active against both developmental stages, particularly the somules, for which the inhibitor was the most potent of 11 inhibitors tested (multiple phenotypic changes noted at 1 μM after 24 h). This is perhaps not surprising, as GW843682X was an early tool molecule with modest cellular activity, whereas GSK461364 was a clinical candidate [ 51 – 53 , 75 , 76 ]. The natural product, thymoquinone, and its synthetically derived analog, poloxin, both of which target the unique polo-box domain of huPLK1 [ 77 ], were also potent anti-schistosomals: thymoquinone exerted preferential activity against adults (a severity score of 2 at 5 μM after 5 h).…”

Section: Resultsmentioning

confidence: 99%

“…GSK461364 has successfully completed Phase I clinical trials for treatment of specific advanced solid tumors and Non-Hodgkin’s Lymphoma [ 83 ]. The clinical progress of GSK461364 along with the recent availability of 38 structurally related benzimidazole thiophenes within GSK’s PKIS 1 and 2 libraries [ 50 – 53 ] prompted us to explore: (i) whether more effective inhibitors than GSK461364 against the parasite exist, (ii) whether an SAR for anti-parasitic activity could be identified, and (iii) whether any SAR was similar to that demonstrated for huPLK1 by previous GSK research [ 51 – 53 ]. Satisfying the first two conditions would be of interest in having introduced and characterized a new anti-schistosomal chemotype yet, in the absence of particular knowledge of the molecular target or mechanism of action, would create a more challenging, but not insurmountable (e.g., [ 84 – 87 ]), situation for chemical optimization.…”

Section: Discussionmentioning

confidence: 99%

“…Meeting all three conditions, however, would support a decision to initiate a target-based SAR program centered on SmPLK1 which would include recombinant expression, purification and crystallography of SmPLK1 in order to drive the iterative chemical optimization process. Such a program would be aided by the considerable metabolism and toxicity data that are available for many of the benzimidazole thiophenes [ 52 , 53 ].…”

Section: Discussionmentioning

confidence: 99%

“…One of these, a phase I clinical candidate benzimidazole thiophene inhibitor from GlaxoSmithKline (GSK), was bioactive at low micromolar concentrations. This inhibitor served as a starting point for a phenotypic screen of 38 benzimidazole thiophene analogs contained within GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2 [ 50 – 53 ]. We identify a structure-activity relationship (SAR) for this inhibitor set that is shared between somules and adult parasites, and we discuss our findings with a view to the possible future development of this compound class as a source of novel anti-schistosomals.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

et al. 2016

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BackgroundSchistosoma flatworm parasites cause schistosomiasis, a chronic and debilitating disease of poverty in developing countries. Praziquantel is employed for treatment and disease control. However, its efficacy spectrum is incomplete (less active or inactive against immature stages of the parasite) and there is a concern of drug resistance. Thus, there is a need to identify new drugs and drug targets.Methodology/Principal FindingsWe show that RNA interference (RNAi) of the Schistosoma mansoni ortholog of human polo-like kinase (huPLK)1 elicits a deleterious phenotypic alteration in post-infective larvae (schistosomula or somules). Phenotypic screening and analysis of schistosomula and adult S. mansoni with small molecule inhibitors of huPLK1 identified a number of potent anti-schistosomals. Among these was a GlaxoSmithKline (GSK) benzimidazole thiophene inhibitor that has completed Phase I clinical trials for treatment of solid tumor malignancies. We then obtained GSKs Published Kinase Inhibitor Sets (PKIS) 1 and 2, and phenotypically screened an expanded series of 38 benzimidazole thiophene PLK1 inhibitors. Computational analysis of controls and PLK1 inhibitor-treated populations of somules demonstrated a distinctive phenotype distribution. Using principal component analysis (PCA), the phenotypes exhibited by these populations were mapped, visualized and analyzed through projection to a low-dimensional space. The phenotype distribution was found to have a distinct shape and topology, which could be elicited using cluster analysis. A structure-activity relationship (SAR) was identified for the benzimidazole thiophenes that held for both somules and adult parasites. The most potent inhibitors produced marked phenotypic alterations at 1–2 μM within 1 h. Among these were compounds previously characterized as potent inhibitors of huPLK1 in cell assays.Conclusions/SignificanceThe reverse genetic and chemical SAR data support a continued investigation of SmPLK1 as a possible drug target and/or the prosecution of the benzimidazole thiophene chemotype as a source of novel anti-schistosomals.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

et al. 2016

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“…The corresponding products, xylitol and ( S )-1-(2-chlorophenyl)ethanol, are used in food-processing and pharmaceutical industry. The alternative food sweetener xylitol is produced in ton scale and chiral 1-(2-chlorophenyl)ethanols are key intermediates in the synthesis of a novel class of chemotherapeutic substances (PLK1 kinase inhibitors; [18-20]).…”

Section: Resultsmentioning

confidence: 99%

Host cell and expression engineering for development of an E. coli ketoreductase catalyst: Enhancement of formate dehydrogenase activity for regeneration of NADH

et al. 2012

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BackgroundEnzymatic NADH or NADPH-dependent reduction is a widely applied approach for the synthesis of optically active organic compounds. The overall biocatalytic conversion usually involves in situ regeneration of the expensive NAD(P)H. Oxidation of formate to carbon dioxide, catalyzed by formate dehydrogenase (EC 1.2.1.2; FDH), presents an almost ideal process solution for coenzyme regeneration that has been well established for NADH. Because isolated FDH is relatively unstable under a range of process conditions, whole cells often constitute the preferred form of the biocatalyst, combining the advantage of enzyme protection in the cellular environment with ease of enzyme production. However, the most prominent FDH used in biotransformations, the enzyme from the yeast Candida boidinii, is usually expressed in limiting amounts of activity in the prime host for whole cell biocatalysis, Escherichia coli. We therefore performed expression engineering with the aim of enhancing FDH activity in an E. coli ketoreductase catalyst. The benefit resulting from improved NADH regeneration capacity is demonstrated in two transformations of technological relevance: xylose conversion into xylitol, and synthesis of (S)-1-(2-chlorophenyl)ethanol from o-chloroacetophenone.ResultsAs compared to individual expression of C. boidinii FDH in E. coli BL21 (DE3) that gave an intracellular enzyme activity of 400 units/gCDW, co-expression of the FDH with the ketoreductase (Candida tenuis xylose reductase; XR) resulted in a substantial decline in FDH activity. The remaining FDH activity of only 85 U/gCDW was strongly limiting the overall catalytic activity of the whole cell system. Combined effects from increase in FDH gene copy number, supply of rare tRNAs in a Rosetta strain of E. coli, dampened expression of the ketoreductase, and induction at low temperature (18°C) brought up the FDH activity threefold to a level of 250 U/gCDW while reducing the XR activity by just 19% (1140 U/gCDW). The E. coli whole-cell catalyst optimized for intracellular FDH activity showed improved performance in the synthesis of (S)-1-(2-chlorophenyl)ethanol, reflected in a substantial, up to 5-fold enhancement of productivity (0.37 g/gCDW) and yield (95% based on 100 mM ketone used) as compared to the reference catalyst. For xylitol production, the benefit of enhanced FDH expression was observed on productivity only after elimination of the mass transfer resistance caused by the cell membrane.ConclusionsExpression engineering of C. boidinii FDH is an important strategy to optimize E. coli whole-cell reductase catalysts that employ intracellular formate oxidation for regeneration of NADH. Increased FDH-activity was reflected by higher reduction yields of D-xylose and o-chloroacetophenone conversions provided that mass transfer limitations were overcome.

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Photobiocatalyzed asymmetric reduction of ketones using Chlorella sp. MK201

Itoh

Nakamura²,

Aoyama³

et al. 2012

Biotechnol Lett

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Aromatic ketones were reduced using suspension culture of Chlorella sp. MK201 under fluorescent light illumination producing the corresponding chiral alcohols in high yields with excellent enantiomeric excess (ee). For example, 2',3',4',5',6'-pentafluoroacetophenone at 0.25 mg/ml was converted to the corresponding (S)-alcohol in 80 % yield with >99 % ee by 1 mg dry wt of Chlorella/ml in 12 h illumination (2,000 lux).

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Heteroaryl-linked 5-(1H-benzimidazol-1-yl)-2-thiophenecarboxamides: Potent inhibitors of polo-like kinase 1 (PLK1) with improved drug-like properties

Cited by 15 publications

References 23 publications

Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

Structure-Bioactivity Relationship for Benzimidazole Thiophene Inhibitors of Polo-Like Kinase 1 (PLK1), a Potential Drug Target in Schistosoma mansoni

Host cell and expression engineering for development of an E. coli ketoreductase catalyst: Enhancement of formate dehydrogenase activity for regeneration of NADH

Photobiocatalyzed asymmetric reduction of ketones using Chlorella sp. MK201

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